(Last
modification:
06. March 2010)
References for Resveratrol Publications
(certainly not complete!)
Oktober 2008:
Prof. Harald zur Hausen, Winner of
the
Nobel Prize in Medicine 2008,
in an interview with the Journal "Spiegel", about possible chemo-prevention of
cancer: 'Es
gibt eine ganze Fülle von Substanzen, die vielversprechend aussehen, etwa die
Polyphenole. Der bekannteste dieser Stoffe ist das Resveratrol, eine oft
gepriesenes Wundermittel im Rotwein'. Im weiteren Verlauf des Interviews
sagt er auch, dass sich diese Substanzen im Tierversuch als wirksam erwiesen
haben. Sie wirken auch in den Herzkreislauf hinein und sogar in den
Alterungsprozess. Er weist er aber auch klar darauf hin, dass diese Stoffe in
reiner Form nicht ohne weiteres beim Menschen anzuwenden sind, weil sie oft
toxisch sind und zu Leberschäden führen.
A rough English
translation:
Re cancer
chemo-prevention: there is a large number of substances that look
promising, for example the polyphenols. The most well-known is resveratrol, an
often acclaimed "wonder drug" in red wine. In the further course of the
interview he also states that these substances proved to be effective in animal
trials; they are active in metabolism and ageing processes. However, he
also pointed out clearly that these substances in pure form might be harmful,
because in larger amounts they might be toxic and might lead to liver damage.
Quelle/Source:
'Der Spiegel', Nr. 42/13.10.2008, Interview mit Prof. H. zur Hausen, Seite
165
More about
Prof. zur Hausen is
here.
A few links to Internet
Pages
-
The German weekly Journal 'Der Spiegel' picked up the topic with an article:
(apparently no longer available, March 2010)
"Heilkraft des Hungerns", also named in the contents list: "US-Forscher entwickeln eine Jungbrunnenpille".
The article discusses the effects of a low-calorie-diet
(see also the
Wikipedia
page on Calorie Restriction), and the possible effects of resveratrol. It ends with the sentences: "Ein Liter Rotwein enthält maximal 15 Milligramm der vermeintlichen Zaubersubstanz Resveratrol. Wer auf die in den Mäusen erfolgreiche Dosis kommen wollte, müsste jeden Tag mindestens 150 Flaschen leeren".
A free translation: 'One liter of red wine contains maximally 15 mg of the putatively magic substance resveratrol. If you want to reach the dosis successful in mice: you would have to empty at least 150 bottles per day'. This is the sort of flashy end the Journal loves, but it ignores that the calculation applied here is not very meaningful.
Obviously the author used the body mass relation for calculating the necessary dosis: 15 mg x 150 bottles (each 1 Liter!) red wine would contain 2250 mg Resveratrol (i.e. just about the dosis calculated from the mice experiments,
taking simply the increased human body mass). Actually, using the standard conversion factor from mice to men (0.08,
more...), "just" 12 bottles would be sufficient. Still, that is considerably more than most of us would consider meaningful in any way, is it not?
Citation: 'The Spiegel', issue 50, pp. 154-156, Date: 11. December 2006. Unfortunately,
no longer available, apparently . Too bad! (Well, maybe not: such loose talking is not very helpful to the interested layman,
in particular as it shows that the author did not research properly).
It is noteworthy that the Spiegel had a previous article on resveratrol (02. November 2006). The author was a bit more cautious (and imprecise) with respect to the dosis of resveratrol: 'Dosis entspricht Dutzenden Flaschen Rotwein' (translated: 'dosis corresponds to dozens of bottles of red wine'). The article appears to be freely accessible: http://www.spiegel.de/wissenschaft/mensch/0,1518,445789,00.html. -
And look at that: Resveratrol synthesis in transgenic plants, Bakers yeast, and even animal cell cultures:
More..
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Please note: this
goes only up to 2007:
more up to date references are
here
Selected Overviews
See some more referencess:
More...
Athar, M., Back, J. H., Tang, X., Kim, K. H., Kopelovich, L., Bickers, D. R., Kim, A. L., 2007.
Resveratrol: a review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology 224, 274-283.
The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.
Access to free author manuscript in PubMed Central: more...
Couzin, J., 2004. Scientific community. Aging research's family feud. Science 303, 1276-1279.
Bianchini, F., Vainio, H., 2003. Wine and resveratrol: mechanisms of cancer prevention? European Journal of Cancer Prevention 12, 417-425.
Low alcohol consumption seems to decrease total mortality and to have beneficial properties on cardiovascular disease; data for cancer are still inconclusive. There is evidence that wine consumption decreases the risk of cancer at several sites, including cancer of upper digestive tract, lung, colon, basal cell carcinoma, and non-Hodgkin lymphoma. The presence of resveratrol, a polyphenol specifically present in red wine, may contribute to these cancer preventive effects. Resveratrol in fact inhibits the metabolic activation of carcinogens, has antioxidant and anti-inflammatory properties, decreases cell proliferation and induces apoptosis. Data on the availability of resveratrol in vivo are however still lacking. Although regular consumption of one or two glasses of wine seems reasonably safe from the health point of view, a recommendation to the general population for low wine consumption is not justified.
Pervaiz, S., 2003. Resveratrol: from grapevines to mammalian biology. FASEB Journal 17, 1975-1985.
Hall, S. S., 2003. Longevity research. In vino vitalis? Compounds activate life-extending genes. Science 301, 1165.
Dong, Z., 2003. Molecular mechanism of the chemopreventive effect of resveratrol. Mutat. Res. 523/524, 145-150.
Chemoprevention is a promising approach to control human cancer. Resveratrol has been shown to have a potent chemopreventive effect in multiple carcinogenesis models. However, the precise mechanism explaining its anti-carcinogenic effect is not clear. This review summarizes recent studies from our laboratory on the mechanisms of resveratrol's effects. In JB6 cells, resveratrol was found to induce apoptosis and inhibit tumor promoter -induced cell transformation. We also found that resveratrol -induced activation of p53 and resveratrol-induced apoptosis occurred through a p53-dependent pathway. The MAP kinases, ERKs, JNKs, or p38 kinases, are involved in resveratrol-induced activation of p53 and apoptosis.
Burns, J., Yokota, T., Ashihara, H., Lean, M. E. J., Crozier, A., 2002. Plant foods and herbal sources of resveratrol. Journal of Agricultural and Food Chemistry 50, 3337-3340.
Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.
Fremont, L., 2000. Biological effects of resveratrol. Life Sciences 66, 663-673.
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occuring phytoalexin produced by some spermatophytes, such as grapevines, in response to injury. Given that it is present in grape berry skins but not in flesh, white wine contains very small amounts of resveratrol, compared to red wine. The concentrations in the form of trans- and cis- isomers of aglycone and glucosides are subjected to numerous variables. In red wine, the concentrations of the trans-isomer, which is the major form, generally ranges between 0.1 and 15 mg/L. As phenolic compound, resveratrol contributes to the antioxidant potential of red wine and thereby may play a role in the prevention of human cardiovascular diseases. Resveratrol has been shown to modulate the metabolism of lipids, and to inhibit the oxidation of low-density lipoproteins and the aggregation of platelets. Moreover, as phytoestrogen, resveratrol may provide cardiovascular protection. This compound also possesses anti-inflammatory and anticancer properties. However, the bioavailability and metabolic pathways must be known before drawing any conclusions on the benefits of dietary resveratrol to health.
Kopp, P., 1998. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? Eur. J. Endocrinol. 138, 619-620.
Certain populations, e.g. the French and the Greek, suffer little heart disease despite a diet which is relatively high in fat. It has been proposed that regular consumption of red wine in moderate amounts may explain this phenomenon, which has been dubbed the `French paradox'. Resveratrol, a compound found in grapes and wine in significant amounts, was implicated to play a role in this beneficial action of red wine because of its ability to act as an antioxidant and an inhibitor of platelet-aggregation. In addition, resveratrol has been reported to have anticarcinogenic effects in mouse mammary cultures.
Return to Resveratrol overview
Constant, J., 1997. Alcohol, ischemic heart disease, and the
French paradox. Coronary Artery Disease 8, 645-649.
Studies comparing alcohol intake and ischemic heart disease have shown either an inverse relation or a U-shaped curve in which the equivalent of two drinks per day of any kind of alcohol is associated with a decreased incidence of coronary disease compared with no drinks, while higher doses result in an increased risk of infarction and stroke. The cardioprotective effects of most alcoholic beverages are probably due to an elevation of high-density lipoprotein and the ability of alcohol to prevent platelet aggregation and increase fibrinolysis; however, there is an increased favorable effect from red wine. The unique cardioprotective properties of red wine reside in the action of flavonoids which are minimal in white wine (with the exception of champagne). The best researched flavonoids are resveratrol and quercetin, which confer antioxidant properties more potent than alpha-tocopherol. Grape juice has about half the amount of flavonoids by volume as red wine.
Return to Resveratrol overview
Soleas, G. J., Diamandis, E. P., Goldberg, D. M., 1997. Resveratrol: a molecule whose time has come? And gone? Clinical Biochemistry 30, 91-113.
Resveratrol (3,5,4'-trihydroxystilbene) is the parent compound of a family of molecules, including glucosides and polymers, existing in cis and trans configurations in a narrow range of spermatophytes of which vines, peanuts and pines are the prime representatives. Its synthesis from p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection or UV- irradiation, and it is classified as a phytoalexin anti-fungicide conferring disease resistance in the plant kingdom.
In vitro, ex vivo and animal experiments have shown that it possesses many biological attributes that favour protection against atherosclerosis, including antioxidant activity, modulation of hepatic apolipoprotein and lipid synthesis, inhibition of platelet aggregation as well as the production of pro-atherogenic eicosanoids by human platelets and neutrophils. Red wine represents its main source in the human diet, and it has been proposed as a major constituent of the polyphenol fraction to which the health benefits of red wine consumption have been attributed.
The past several years have witnessed intense research devoted to its measurement in wine and the factors likely to promote its enrichment in this beverage. Up to the present, conclusive evidence for its absorption by human subjects in biologically significant amounts is lacking, and it is questionable (but not yet excluded) that its powerful and beneficial in vitro activities are reproduced as a consequence of sustained moderate red wine consumption.
Soleas, G.J., Diamandis, E.P. and Goldberg, D.M., 1997. Wine as a biological fluid: history, production, and role in disease prevention. J. Clin. Lab. Analysis 11, 287-313.
Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.
Rimm, E.B., Klatsky, A., Grobbee, D. and Stampfer, M.J., 1996. Review of moderate alcohol consumption and reduced risk of coronary heart disease - is the effect due to beer, wine, or spirits. British Medical Journal 312, 731-736.
Objectives: To review the effect of specific types of alcoholic drink on coronary risk. Design-Systematic review of ecological, case-control, and cohort studies in which specific associations were available for consumption of beer, wine, and spirits and risk of coronary heart disease. Subjects-12 ecological, three case-control, and 10 separate prospective cohort studies. Main outcome measures-Alcohol consumption and relative risk of morbidity and mortality from coronary heart disease.
Results: Most ecological studies suggested that wine was more effective in reducing risk of mortality from heart disease than beer or spirits. Taken together, the three case-control studies did not suggest that one type of drink was more cardioprotective than the others. Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found such an association for beer, and four for spirits.
Conclusions: Results from observational studies, where alcohol consumption can be linked directly to an individual's risk of coronary heart disease, provide strong evidence that all alcoholic drinks are linked with lower risk. Thus, a substantial portion of the benefit is from alcohol rather than other components of each type of drink.
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Selected Original Papers -
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., Pistell, P. J., Poosala, S., Becker, K. G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K. W., Spencer, R. G., Lakatta, E. G., Le Couteur, D., Shaw, R. J., Navas, P., Puigserver, P., Ingram, D. K., De Cabo, R., Sinclair, D. A., 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature,
444, 337-342 (16 November 2006)
Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 alpha (IGF-I alpha) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor- coactivator 1 (PGC-1) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L. L., Scherer, B., Sinclair, D. A., 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196.
In diverse organisms, calorie restriction slows the pace of aging and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
Comments to this article:
Corder, R., Crozier, A., Kroon, P. A., 2003. Drinking your health? It's too early to say. Nature 426, 119
Finkel, T., 2003. Ageing: a toast to long life. Nature 425, 132-133.
Return to Resveratrol Bradamante, S., Barenghi, L., Piccinini, F., Bertelli, A. A. E., De Jonge, R., Beemster, P., De Jong, J. W., 2003. Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. European Journal of Pharmacology 465, 115-123.
We used two experimental models to prove that resveratrol (trans-3,4',5-trihydroxystilbene) reduces cardiac ischemic-reperfusion injury by means of a nitric oxide- and adenosine-dependent mechanism. (1) Acute ex vivo: resveratrol (10 µM, 10 min) infusion in Langendorff-perfused normoxic rat hearts significantly increased adenosine release and coronary flow compared with baseline. After 30-min low-flow ischemia, vasodilation, still present at reperfusion, was completely abolished by resveratrol plus adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT, 50 µM) administration. (2) Chronic in vivo: rats received tap water containing 25 mg/l resveratrol for 15 days or normal water. Twenty-four hours after, their hearts were Langendorff-perfused and submitted to 60-min low-flow ischemia and reperfusion. The resveratrol-treated hearts showed better functional recovery at reperfusion and significant vasodilation, but no variation in high-energy phosphates (31P Nuclear Magnetic Resonance). NG-nitro--arginine methyl ester (-NAME, 30 µM), a nonselective nitric oxide synthase inhibitor, or SPT (50 µM) administered for 10 min prior to the low-flow ischemia cancelled the effects. This suggests that long-term moderate resveratrol consumption could play an important role in late cardioprotective effects. Matsuoka, A., Takeshita, K., Furuta, A., Ozaki, M., Fukuhara, K., Miyata, N., 2002. The 4'-hydroxy group is responsible for the in vitro cytogenetic activity of resveratrol. Mutation Research 521, 29-35.
We previously reported that 3,5,4'-trihydroxy-trans-stilbene (resveratrol), a polyphenolic phytoalexin found in grapes, induces a high frequency of sister chromatid exchanges (SCEs) in vitro. In this study, to investigate structure activity relationships, we synthesized six analogues of resveratrol differing in number and position of hydroxy groups, and we investigated their activity in chromosomal aberration (CA), micronucleus (MN) and sister chromatid exchange (SCE) tests in a Chinese hamster cell line (CHL). Two of the six analogues (3,4'-dihydroxy-trans-stilbene and 4-hydroxy-trans-stilbene) showed clear positive responses in a concentration-dependent manner in all three tests. Both were equal to or stronger than resveratrol in genotoxicity. The 4'-hydroxy (OH) analogue had the simplest chemical structure and was the most genotoxic. The other analogues did not have a 4'-hydroxy group. These results suggested that a 4'-hydroxy group is essential to the genotoxicity of stilbenes. Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K., Forstermann, U., 2002. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106, 1652-1658.
Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1. Resveratrol, a polyphenolic phytoalexin found in grapes and wine, has been reported to act as an agonist at the estrogen receptor. Therefore, we tested the effect of this putative phytoestrogen on eNOS expression in human endothelial cells.
Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol for 24 to 72 hours upregulated eNOS mRNA expression in a time- and concentration-dependent manner (up to 2.8-fold). eNOS protein expression and eNOS-derived NO production were also increased after long-term incubation with resveratrol. Resveratrol increased the activity of the eNOS promoter (3.5-kb fragment) in a concentration-dependent fashion, with the essential trans-stimulated sequence being located in the proximal 263 bp of the promoter sequence. In addition, eNOS mRNA was stabilized by resveratrol. The effect of resveratrol on eNOS expression was not modified by the estrogen receptor antagonists ICI 182780 and RU 58668. In electrophoretic mobility shift assays, nuclear extracts from resveratrol-incubated EA.hy 926 cells showed no enhanced binding activity of the eNOS promoter-relevant transcription factors Sp1, GATA, PEA3, YY1, or Elf-1. In addition to its long-term effects on eNOS expression, resveratrol also enhanced the production of bioactive NO in the short-term (after a 2-minute incubation).
In concert with other effects, the stimulation of eNOS expression and activity may contribute to the cardiovascular protective effects attributed to resveratrol. Yu, C. W., Shin, Y. G., Chow, A., Li, Y. M., Kosmeder, J. W., Lee, Y. S., Hirschelman, W. H., Pezzuto, J. M., Mehta, R. G., Van Breemen, R. B., 2002. Human, rat, and mouse metabolism of resveratrol. Pharmaceutical Research 19, 1907-1914.
Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of transresveratrol were investigated. Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed- phase highperformance liquid chromatography with on- line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD- MS and LC- UV- MS- MS). UV- photodiode array analysis facilitated the identification of cis- and trans- isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained.
No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans- resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with beta- glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis- resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol.
Our results indicate that trans- resveratrol- 3- O-glucuronide and trans- resveratrol- 3- sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol. Laden, B. P., Porter, T. D., 2001. Resveratrol inhibits human squalene monooxygenase. Nutrition Research 21, 747-753.
Epidemiological studies have suggested that moderate consumption of red wine may protect against the development of cardiovascular diseases. Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound found in a variety of sources, including red wine, that has been shown to have a number of beneficial effects on cardiovascular health, including prevention of oxidative damage, promotion of vasodilation, and prevention of platelet aggregation. Herein we report that resveratrol specifically inhibits purified human squalene monooxygenase, a rate-limiting enzyme in cholesterol biosynthesis, in a noncompetitive manner with respect to both squalene (Ki = 35 µM) and FAD (Ki = 69 µM). These data raise the possibility that the protective effect of resveratrol on the development of cardiovascular disease may be explained in part by the inhibition of endogenous cholesterol biosynthesis. Chan, W. K., Delucchi, A. B., 2000. Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4. Life Sciences 67, 3103-3112.
Resveratrol, a phytoalexin found in red wine, has been shown to possess antioxidant and antimutagenic properties. Incubation of resveratrol with Sf9 insect microsomes containing baculovirus-derived human cytochrome P450 3A4 (CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactivated CYP3A4 in a time- and NADPH-dependent manner. Resveratrol, erythromycin and troleandomycin inactivated CYP3A4 at a similar rate (as reflected by k(inact)) whereas the binding affinity to CYP3A4 (as reflected by KI) was in the order of: troleandomycin > erythromycin > resveratrol, (KI and k(inact) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomycin are 20 µM and 0.20 min(-1), 5.3 µM and 0.12 min(-1) and 0.18 µM and 0.15 min(-1), respectively.) Fractionation studies of red wine showed that fractions that did not contain resveratrol inactivated CYP3A4 significantly. In addition, the resveratrol content in red wine used in the study was too low to account for the degree of CYP3A4 inactivation observed after red wine treatment. Inactivation studies using a variety of red wine types showed that the CYP3A4 inactivation did not correlate to their resveratrol content. In summary, data here showed that resveratrol is an effective mechanism-based inactivator of CYP3A4; however, it is not one of the main red wine constituents that are responsible for CYP3A4 inactivation by red wine. Nevertheless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates. Chun, Y. J., Kim, M. Y., Guengerich, F. P., 1999. Resveratrol is a selective human cytochrome P450 1A1 inhibitor. Biochemical and Biophysical Research Communications 262, 20-24.
Resveratrol (trans-3,4',5-trihydroxystilbene) is a phytoalexin compound found in juice and wine produced from dark-skinned grape cultivars and reported to have anti-inflammatory and anticarcinogenic activities. To investigate the mechanism of anticarcinogenic activities of resveratrol, the effects on cytochrome P450 (P450) were determined in human liver microsomes and Escherichia coli membranes coexpressing human P450 1A1 or P450 1A2 with human NADPH-P450 reductase (bicistronic expression system). Resveratrol slightly inhibited ethoxyresorufin O-deethylation (EROD) activity in human liver microsomes with an IC50 of 1.1 mM. Interestingly, resveratrol exhibited potent inhibition of human P450 1A1 in a dose-dependent manner with IC50 of 23 µM for EROD and IC50 of 11 µM for methoxyresorufin O- demethylation (MROD). However, the inhibition of human P450 1A2 by resveratrol was not so strong (IC50 1.2 mM for EROD and 580 µM for MROD). Resveratrol showed over 50-fold selectivity for P450 1A1 over P450 1A2. The activities of human NADPH-P450 reductase were not significantly changed by resveratrol. In a human P450 1A1/reductase bicistronic expression system, resveratrol inhibited human P450 1A1 activity in a mixed-type inhibition (competitive-noncompetitive) with a Ki values of 9 and 89 µM. These results suggest that resveratrol is a selective human P450 1A1 inhibitor, and may be considered for use as a strong cancer chemopreventive agent in humans. Frémont, L., Belguendouz, L., Delpal, S., 1999. Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sciences 64, 2511-2521.
Wine polyphenols were examined for their capacity to protect the lipid and protein moieties of porcine low density lipoproteins (LDL) during oxidation. The efficiency of resveratrol (3,4';5-trihydroxystilbene) and defined flavonoids was compared to that of a wine extract (WE) containing 0.5 g/g proanthocyanidols. The efficiency of resveratrol for protecting polyunsaturated fatty acids (PUFA) was higher than that of flavonoids in copper-induced oxidation and lower in AAPH (radical initiator)induced oxidation. The LDL receptor activity was evaluated by now cytometry using LDL labeled with fluorescein isothiocyanate (FITC) and Chinese hamster ovary cells (CHO-K-1). The incubation of CHO-K-1 with FITC-LDL oxidized for 16 h reduced the proportion of fluorescent cells from 97% to 4%. At a concentration of 40 µM, resveratrol and flavonoids completely restored the uptake of copper-oxidized LDL and AAPH-oxidized LDL respectively. Total fluorescence could also be obtained with 20 mg/L of WE with both oxidation systems. These data are consistent with previous findings relative to the formation of degradative products from PUFA. They confirm that resveratrol was more effective than flavonoids as a chelator of copper and less effective as a free-radical scavenger. Moreover, they show that WE, which contained monomeric and oligomeric forms of flavonoids and phenolic acids, protected LDL by both mechanisms. Huang, C. S., Ma, W. Y., Goranson, A., Dong, Z. G., 1999. Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis 20, 237-242.
Resveratrol, a plant constituent enriched in the skin of grapes, is one of the most promising agents for the prevention of cancer. However, the mechanism of the anti-carcinogenic activity of resveratrol is not well understood. Here we offer a possible explanation of its anti-cancer effect. Resveratrol suppresses tumor promoter-induced cell transformation and markedly induces apoptosis, transactivation of p53 activity and expression of p53 protein in the same cell line and at the same dosage, Also, resveratrol-induced apoptosis occurs only in cells expressing wild-type p53 (p53(+/+)), but not in p53-deficient (p53(-/-)) cells, while there is no difference in apoptosis induction between normal lymphoblasts and sphingomyelinase-deficient cell lines. These results demonstrate for the first time that resveratrol induces apoptosis through activation of p53 activity, suggesting that its anti-tumor activity may occur through the induction of apoptosis. Clément, M. V., Hirpara, J. L., Chawdhury, S. H., Pervaiz, S., 1998. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 92, 996-1002.
Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression an HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of: the CD95-CD95L system in the anti- cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity. Fontecave, M., Lepoivre, M., Elleingand, E., Gerez, C., Guittet, O., 1998. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Letters 421, 277-279.
Resveratrol, a natural phytoalexin found in grapes, is well known for its presumed role in the prevention of heart disease, associated with red wine consumption. We show here that it is a remarkable inhibitor of ribonucleotide reductase and DNA synthesis in mammalian cells, which might have further applications as an antiproliferative or a cancer chemopreventive agent in humans. Gehm, B. D., McAndrews, J. M., Chien, P. Y., Jameson, J. L., 1997. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proceedings of the National Academy of Sciences of the United States of America 94, 14138-14143.
The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (3-10 µM) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells. This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol. Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems. The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine. Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., Pezzuto, J. M., 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-220.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
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